Oral Absorption of Ginsenoside Rb₁ using in vitro and in vivo Models

Abstract

This research attempts to clarify the cause for poor oral absorption of ginsenoside Rb₁ (Rb₁), one main ingredient of the well known Panax notoginseng saponins (PNS) for curing hemorrhage. Caco-2 cell monolayers were used as an in vitro model to reveal the transport mechanism of Rb₁ across the intestinal mucosa. Moreover, the serum concentration-time profiles of Rb₁ after tail venous (IV), portal venous (PV), intraduodenal (ID) and peroral (PO) administration to rats were compared to evaluate the first-pass effects of stomach, intestine and liver. In vitro experiments showed that uptake by Caco-2 cell monolayers was temperature dependent, but was not influenced by cyclosporine A and ketoconazole. The change in the apical pH showed no obvious effects on the uptake of Rb₁. The uptake and transport were non-saturable, and flux from the apical compartment to the basolateral compartment (A - B) increased linearly with increasing concentration, which indicated a passive transport. Meanwhile, an apparent permeability coefficient of (5.90 ± 1.02) × 10^-8 cm/s (C₀ = 1 mg/mL) predicted an incomplete absorption. The investigation on the pharmacokinetic behavior of Rb₁ after different routes of administration to rats showed a significant difference between PO (F_PO was 0.64 %), ID (F_ID was 2.46 %) and PV (F_PV was 59.49 %) administration, and the first-pass effect of the intestine is more significant than that of the stomach and liver in the absorption process. In summary, elimination in the stomach, large intestine and liver contributed to the poor absorption of Rb₁, but the low membrane permeability might be a more important factor dominating the extent of absorption.

Abbreviations

Rb₁:ginsenoside Rb₁

PNS:Panax notoginseng

A:apical

B:basolateral

HEPES:N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

MES:2-N-morpholineethanesulfonic acid

HBSS:Hanks balanced salt solution

CsA:cyclosporine A

KCZ:ketoconazole

P_app:apparent permeability coefficient

PO:peroral (administration)

ID:intraduodenal (administration)

PV:portal venous (administration)

IV:tail venous (administration)

F_PO:absolute bioavailability after peroral administration

F_ID:absolute bioavailability after intraduodenal administration

F_PV:absolute bioavailability after portal venous administration

F_IV:absolute bioavailability after tail venous administration

Key words

Ginsenoside Rb₁ - Panax notoginseng - Caco-2 - bioavailability

References

• 1 Guan L, Li W, Liu Z. Effect of ginsenoside-Rb₁ on cardiomyocyte apoptosis after ischemia and reperfusion in rats.  J Huazhong University Sci Technol Med Sci. 2002;  22 212-5
• 2 Park K H, Shin H J, Song Y B, Hyun H C, Cho H J, Ham H S. et al . Possible role of ginsenoside Rb₁ on regulation of rat liver triglycerides.  Biol Pharm Bull. 2002;  25 457-60
• 3 Chen Y S, Wu C H, Yao C H, Chen C T. Ginsenoside Rb₁ enhances peripheral nerve regeneration across wide gaps in silicone rubber chambers.  Int J Artif Organs. 2002;  25 1103-8
• 4 Park J K, Namgung U K, Lee C J, Park J O, Jin S H, Kwon O B. et al . Calcium-independent CaMKII activity is involved in ginsenoside Rb₁-mediated neuronal recovery after hypoxic damage.  Life Sci. 2005;  76 1013-25
• 5 Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. VII. Comparison of the decomposition modes of ginsenoside-Rb₁ and Rb₂ in the digestive tract of rats.  Chem Pharm Bull. 1991;  39 2357-61
• 6 Akao T, Kida H, Kanaoka M, Hattori M, Kobashi K. Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb₁ from Panax ginseng .  Pharm Pharmacol. 1998;  50 1155-60
• 7 Bae E A, Park S Y, Kim D H. Constitutive beta-glucosidases hydrolyzing ginsenoside Rb₁ and Rb₂ from human intestinal bacteria.  Biol Pharm Bull. 2000;  23 1481-5
• 8 Hasegawa H, Sung J H, Benno Y. Role of human intestinal Prevotella oris in hydrolyzing ginseng saponins.  Planta Med. 1997;  63 436-40
• 9 Odani T, Tanizawa H, Takino Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. III. The absorption, distribution and excretion of ginsenoside Rb₁ in the rat.  Chem Pharm Bull. 1983;  31 1059-66
• 10 Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport.  Adv Drug Deliv Rev. 2001;  46 27-43
• 11 Yamada K, Murakami M, Yamamoto A, Takada K, Muranishi S. Type hepatic uptake of liposomes in the rat.  J Pharm Pharmacol. 1992;  44 711-21
• 12 Hidalgo I J, Li J. Carrier-mediated transport and efflux mechanisms in Caco-2 cells.  Adv Drug Deliv Rev. 1996;  22 53-66
• 13 Azuma R, Hirota T, Manabe H, Komuro M, Kiwada H. First-pass of GTS-21 on canine gut wall and liver determined by portal-systemic concentration difference.  Eur J Pharm Sci. 2001;  14 59-65
• 14 Kim S H, Lee M G. Pharmacokinetics of ipriflavone, an isoflavone derivative, after intravenous and oral administration to rats. Hepatic and intestinal first-pass effects.  Life Sci. 2002;  70 1299-315
• 15 Yamaoka K, Nakagava J, Uno T. Statistical moments in pharmacokinetics.  J Pharmacokinet Biopharm. 1978;  6 547-57
• 16 Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells.  Pharm Sci. 2000;  10 195-204
• 17 Xu Q F, Fang X L, Chen D F. Pharmacokinetics and bioavailability of ginsenoside Rb₁ and Rg₁ from Panax notoginseng in rats.  J Ethnopharmacol. 2003;  84 187-92
• 18 Brunet J L, Maresca M, Fantini J, Belzunces L P. Human intestinal absorption of imidacloprid with Caco-2 cells as enterocyte model.  Toxicol Appl Pharmacol. 2004;  192 1-9
• 19 Rubas W, Zezyk N, Grass G M. Comparison of the permeability characterization of human colonic epithelium (Caco-2) cell line to colon of rabbit, monkey and dog intestine and human drug absorption.  Pharm Res. 1993;  10 113-8